The overall goal of this Program Project is to develop an understanding of the biological and molecular biological phenomena which underlie neoplastic disease. To this end we will use the myeloid disorders as model systems and will carefully study normal myelopoiesis, preleukemia, and acute leukemia in order to develop an understanding of the differences among these different states and of the phenomena associated with the development of neoplastic disease. The studies in Project I are designed to precisely characterize myeloid cells with respect to cell lineage and level of maturation using morphologic criteria, histochemical stain, cell surface marker analysis, and electron microscopy. The biologic characteristics of pre-leukemic and leukemic cells in vivo will be defined by the cell cycle and differentiation studies of Project II. Project III is devoted to studying leukemic cell proliferation and differentiation under controlled conditions in vitro. The effect of environmental conditions and hemopoietins will be studied as well. Projects IV and V are devoted to defining the genic phenomena which underlie the biologic phenomena defined in Project I, II, and III. Studies performed during the evolution of preleukemia to leukemia will provide insight into the development of acute leukemia. Project VII will provide the cytogenetic underpinnings of the protooncogene studies and will add data which will compliment more developed in Project I. Project VI is directed towards developing hybrid therapies by combining bioactive reagents with cytotoxic agents and to providing reagents useful for developing new in vitro drug sensitivity assays and for studying proto oncogene expression at the level of the single cell. By integrating the biological and molecular biological data with observations during and after both cytotoxic and bioactive therapies an understanding will be developed of the phenomena associated with response/unresponse to therapy and of the likely course of the diseases being studied. Intensive studies of bioactive agents will be directed towards understanding their effects so that these potentially useful therapies can be introduced into our therapeutic armamentarium.